Drug Photodegradation Research Articles

Laser techniques in the study of drug photochemistry.

This review describes the application of different laser time-resolved techniques, such as time-resolved fluorescence, phosphorescence and laser flash photolysis, to elucidate the mechanism of drug photodegradation. The assignment of transient species based on their luminescence or absorption spectra and based on their reactivity to various quenchers is illustrated. The mathematical expressions used in fitting measured transient decays over time are also discussed. Practical situations found in the literature and relevant to drug photodegradation illustrate different examples. The importance of laser power, concentration and absorbance of the ground state, as well as other parameters intrinsic to laser techniques are discussed.

Triplet-Sensitized Photodegradation of Sulfa Drugs Containing Six-Membered Heterocyclic Groups: Identification of an SO2 Extrusion Photoproduct

The aquatic photochemical behavior of a class of sulfa drugs containing six-membered heterocyclic substituents (sulfamethazine, sulfamerazine, sulfadiazine, sulfachloropyridazine, and sulfadimethoxine) was investigated. Photodegradation of the sulfa drugs in a natural water sample was significantly enhanced relative to the degradation in deionized water, with the exception of sulfadimethoxine. This indicated an indirect photochemical process that was identified through the use of quenchers to be attributable to interaction with triplet excited-state dissolved organic matter (3DOM). The direct photolysis rate constant and quantum yield for both the neutral and anionic species of each sulfa drug were calculated using matrix deconvolution methods. The quantum yield values range from 0.01 x 10(-3) for the neutral form of sulfadimethoxine to 5 x 10(-3) for the anionic form of sulfamethazine and are significantly lower than those observed in a previous study for sulfa drugs containing five-membered heterocyclic substituents, although the rate constants are of similar magnitude. The primary product formed in both direct and indirect photodegradation for all five compounds was identified as a sulfur dioxide extrusion product. The predicted environmental half-lives solely attributable to direct photolysis range from 8.6 h in midsummer at 30 degrees latitude in pH 7 surface water for sulfachloropyridazine to 420 h in midwinter at 45 degrees in pH 7 surface water for sulfadimethoxine. These half-lives, except for sulfadimethoxine, will be decreased by interaction with 3DOM.

Degradation of lincomycin in aqueous medium: Coupling of solar photocatalysis and membrane separation

The photocatalytic oxidation of a common antibiotic, the lincomycin was carried out in aqueous suspensions of polycrystalline TiO 2 Degussa P25 irradiated by sunlight. In order to improve the performance of the lincomycin degradation a hybrid system consisting of a solar photoreactor with the photocatalyst in suspension coupled with a membrane module, used to confine both photocatalyst and pollutants in the reaction environment, was tested. A preliminary study was carried out in order to determine some kinetics parameters of the drug photodegradation. The influence of initial substrate concentration on the lincomycin photooxidation rate was investigated. The photooxidation rate follows a pseudo-first order kinetics with respect to the lincomycin concentration under the used experimental conditions. The presence of the membrane reactor allows the catalyst separation and to operate in continuous mode as the membranes rejection for lincomycin and its oxidation products was quite high.

The Thermal and Photostability of Solid Pharmaceuticals

AbstractFor Abstract see ChemInform Abstract in Full Text.

Vitamin B2-sensitised photooxidation of the ophthalmic drugs Timolol and Pindolol: kinetics and mechanism

The kinetics and mechanistic aspects of the riboflavin-photosensitised oxidation of the topically administrable ophthalmic drugs Timolol (Tim) and Pindolol (Pin) were investigated in water–MeOH (9:1, v/v) solution employing light of wavelength > 400 nm. riboflavin, belonging to the vitamin B2 complex, is a known human endogenous photosensitiser. The irradiation of riboflavin in the presence of ophthalmic drugs triggers a complex picture of competitive reactions which produces the photodegradation of both the drugs and the pigment itself. The mechanism was elucidated employing stationary photolysis, polarographic detection of dissolved oxygen, stationary and time-resolved fluorescence spectroscopy, and laser flash photolysis. Ophthalmic drugs quench riboflavin-excited singlet and triplet states. From the quenching of excited triplet riboflavin, the semireduced form of the pigment is generated, through an electron transfer process from the drug, with the subsequent production of superoxide anion radical (O2•–) by reaction with dissolved molecular oxygen. Through the interaction of dissolved oxygen with excited triplet riboflavin, the species singlet oxygen (O2(1Δg)) is also generated to a lesser extent. Both O2•– and O2(1Δg) induce photodegradation of ophthalmic drugs, Tim being ~3-fold more easily photooxidisable than Pin, as estimated by oxygen consumption experiments.

Effect of binary and ternary polyvinylpyrrolidone and/or hydroxypropyl-β-cyclodextrin complexes on the photochemical and photosensitizing properties of Naproxen

The effect of the polyvinylpyrrolidone and/or hydroxypropyl-β-cyclodextrin on the photolability of aqueous solutions of the anti-inflammatory drug Naproxen was studied. Kinetic studies revealed that the presence of all of these additives reduced drug photodegradation. In all cases, the presence of the different additives elicited a change in the photomixture composition, being the alcoholic derivative the major photoproduct formed. Nevertheless, the change in the efficiency of the process and the amount of the photoproducts formed in the different systems were not related with the biodamage produced by the drug. In this sense, the presence of free Naproxen clearly sensitized the photoperoxidation of linoleic acid. The photosensitizing effect decreased as the PVP concentration increased. Different protection provides the binary (Naproxen:HP-β-CD) and ternary (Naproxen:HP-β-CD:PVP) complexes. The binary complex formation had not effect on the prevention of photooxidation of linoleic acid sensitized by the drug, whereas the ternary complex formation supresses the drug effect. The different behaviour observed with β-CD and HP-β-CD and the structural differences of both cyclodextrins seem to indicate that in the case of the HP-β-CD the linoleic binds with the CD and takes contact with the drug. These results confirm that in these systems the prevention of biodamage would be due to a decrease in the contact between the short-lived species generated during Naproxen photodegradation and biological structures, rather than due to the nature or amount of the photoproducts. In addition, the ability of the complex to interact with the biological structure depends on the structure of both interacting species.

Laser Techniques in the Study of Drug Photochemistry¶

ABSTRACTThis review describes the application of different laser time‐resolved techniques, such as time‐resolved fluorescence, phosphorescence and laser flash photolysis, to elucidate the mechanism of drug photodegradation. The assignment of transient species based on their luminescence or absorption spectra and based on their reactivity to various quenchers is illustrated. The mathematical expressions used in fitting measured transient decays over time are also discussed. Practical situations found in the literature and relevant to drug photodegradation illustrate different examples. The importance of laser power, concentration and absorbance of the ground state, as well as other parameters intrinsic to laser techniques are discussed.

Effect of binary and ternary polyethyleneglycol and/or β-cyclodextrin complexes on the photochemical and photosensitizing properties of Naproxen

The effect of the polyethylene glycol and/or β-cyclodextrin on the photolability of aqueous solutions of the anti-inflammatory drug Naproxen was studied. In all systems studied, the photodegradation process followed zero-order kinetics, leading to the same photoproducts as in the absence of these additives. Kinetic studies revealed that the presence of polyethylene glycol (PEG) reduced drug photodegradation ( Φ=0.11 in water and Φ=0.045 in the presence of 1% of PEG). By contrast, the binary inclusion complex, Naproxen:β-CD, did not protect the drug from degradation, Φ=0.11. However, the ternary complex, Naproxen:β-CD:PEG, reduced the efficiency of the photodegradative process to a considerable extent, with Φ=0.022 in this system. In all cases the presence of the different additives elicited a change in the photomixture composition, the alcoholic derivative being the major photoproduct formed. Nevertheless, the change in the efficiency of the process and the amount of the photoproducts formed in the different systems were not related with the biodamage produced by the drug. In this sense, the presence of free Naproxen clearly sensitized the photoperoxidation of linoleic acid. The photosensitizing effect decreased as the PEG concentration increased and was completely abolished by both the binary (Naproxen:β-CD) and ternary (Naproxen:β-CD:PEG) complexes. In light of these observations, it is possible to speculate that in these systems the prevention of biodamage would be due to a decrease in the contact between the short-lived species generated during Naproxen photodegradation and biological structures, rather than to the nature or amount of the photoproducts.

Laser Techniques in the Study of Drug Photochemistry¶

This review describes the application of different laser time-resolved techniques, such as time-resolved fluorescence, phosphorescence and laser flash photolysis, to elucidate the mechanism of drug photodegradation. The assignment of transient species based on their luminescence or absorption spectra and based on their reactivity to various quenchers is illustrated. The mathematical expressions used in fitting measured transient decays over time are also discussed. Practical situations found in the literature and relevant to drug photodegradation illustrate different examples. The importance of laser power, concentration and absorbance of the ground state, as well as other parameters intrinsic to laser techniques are discussed.

The thermal and photostability of solid pharmaceuticals

Drugs degrade to different extents on separate exposure to heat, moisture, oxidation and light. Combination of these stresses causes very complex behaviour. Many studies have been reported of the thermal behaviour of drugs in the solid-state, but most of the information available on the photodegradation of drugs refers to reactions in solution, (usually aqueous) and photoreactions in the solid-state are even more complex. In drug formulations, the presence of excipients adds further complications because the excipients may increase, have no effect on, or decrease the inherent stabilities of the drug. The literature has been explored to review the thermal and photostabilities of solid pharmaceuticals.

Photostability studies on nicardipine–cyclodextrin complexes by capillary electrophoresis

Nicardipine (NC)–cyclodextrin solid systems were prepared in equimolar ratios and their photostability in aqueous solution under exposure to UV(A)–UV(B) radiations was evaluated. The photodegradation process was monitored by a capillary electrophoresis (CE) method able to provide the enantioresolution of the rac-nicardipine. Enantioresolution was achieved using the mixture 3.0% sulfate-β-cyclodextrin (SβCD) and 2.0% heptakis(2,3,6-tri- O-methyl)-β-cyclodextrin (TMβCD) as chiral selector in 20 mM triethanolammonium phosphate solution (pH 3.0). The photostability studies were carried out on inclusion complexes of rac-nicardipine with α-cyclodextrin (αCD), β-cyclodextrin (βCD), γ-cyclodextrin (γCD), hydroxypropyl-α-cyclodextrin (HPαCD), hydroxypropyl-β-cyclodextrin (HPβCD), hydroxypropyl-γ-cyclodextrin (HPγCD), (2-hydroxyethyl)-β-cyclodextrin (HEβCD) and methyl-β-cyclodextrin (MβCD). A photoprotective effect was observed by βCD, HPαCD, HEβCD, whereas γCD, MβCD, HPβCD and HPγCD did not affect the nicardipine photostability. Conversely, αCD was found to favour the drug photodegradation. Evidences for CD s-mediated stereoselective photodegradation of rac-nicardipine were observed only for the β-CD complex. In this case, two distinct photodegradation profiles, with two different kinetic constants ( k), were observed for the nicardipine enantiomers.

Photostability studies on the furosemide–triamterene drug association

The photostability of the diuretic drugs triamterene and furosemide, individually and combined, was evaluated. Spectrophotometric, spectrofluorimetric and chromatographic (HPLC) methods were applied to monitor the drug photodegradation. Furosemide was confirmed to be highly photolable in both pH 7.4 solution and methanol. Differently triamterene proved to be highly fluorescent (emission quantum yield: 0.9 in methanol and 0.8 in pH 7.4 solution), but essentially photostable (photochemical reaction quantum yield: ≅5×10 −4) under exposure at 365 and 313 nm radiations. When the combined drugs in pH 7.4 solutions were exposed to 365 nm radiations a significant photoprotective effect of triamterene on furosemide was observed. The photoreactivity of the drugs was exploited to develop an HPLC method involving a post-column on-line photochemical derivatization useful to confirm the analyte identity in a commercial dosage form (tablets). The commercial product, containing the combined drugs, proved to be photostable also after long (65 h) light exposure.

Niosomes as carriers for tretinoin: II. Influence of vesicular incorporation on tretinoin photostability

In this work, we compared the chemical stability of tretinoin (TRA) in methanol and in vesicular suspensions exposed both to UV and artificial daylight conditions with the aim of evaluating the potential of niosomes as topical carriers capable of improving the stability of photosensitive drugs. Tretinoin-loaded niosomes were prepared from polyoxyethylene (4) lauryl ether (Brij ® 30), sorbitan esters (Span ® 40 and Span ® 60) and a commercial mixture of octyl/decyl polyglucosides (Triton ® CG110). Liposomes made from hydrogenated (P90H) and non-hydrogenated (P90) soy phosphatidylcholines were also prepared and studied. In order to evaluate the influence of vesicle structure on the photostability of tretinoin, TRA-loaded vesicles were prepared by the film hydration method, extrusion technique and sonication. After UV irradiation, TRA dissolved in methanol degraded very quickly while the incorporation in vesicles always led to a reduction of the photodegradation process. The photoprotection offered by vesicles varied depending on the vesicle structure and composition. After fluorescent light irradiation for 21 days, not all the studied vesicular formulations improved TRA stability when compared with the free drug in methanol. Tretinoin incorporated in P90 or Span vesicles presented a half-life shorter or very close to that of the free drug. However, the inclusion of TRA in P90H liposomes and Brij ® 30 or Triton ® CG110 niosomes retarded the drug photodegradation.

Effect of inclusion complexation with cyclodextrins on photostability of nifedipine in solid state.

Nifedipine is a highly photosensitive drug that requires restricted protection from light during manufacturing, storage and handling of its dosage forms. Inclusion complexation of nifedipine with cyclodextrins (CDs) could be advantageous in protecting the drug against the effect of light. In this study, solid inclusion complexes of nifedipine with beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and dimethyl-beta-cyclodextrin (DM-beta-CD) were prepared using the coprecipitation method. The obtained solid inclusion complexes have been confirmed by differential scanning calorimetry (DSC), X-ray diffraction and infrared spectroscopy (IR). The IR spectra indicated partial inclusion of nifedipine molecules into CD cavities through the dihydropyridine ring. Inclusion complexation was also associated with a dramatic enhancement of drug dissolution with magnitudes depended on the type of CD. The effect of exposure to fluorescent lamp and sunlight on the photodegradation of uncomplexed and complexed nifedipine was tested. Photodegradation of nifedipine was monitored using a high performance liquid chromatographic (HPLC) assay method. Inclusion complexation of nifedipine showed to retard drug photodegradation as indicated by degradation rate constant lowering with values depended on light source and type of complexing agent. This effect was the least with beta-CD compared with that of modified beta-CD. It was also interesting to notice that inclusion complexation of nifedipine offered much higher protection against the effect of fluorescent lamp than that of sunlight. The obtained results suggests that the design of solid dosage forms of nifedipine such as a fast dissolving nifedipine tablets is possible with the advantages of low required light protection.

Evidences of cyclodextrin-mediated enantioselective photodegradation of rac-nicardipine by capillary electrophoresis.

Capillary electrophoresis (CE) was applied to photostability studies on rac-nicardipine, a dihydropyridine chiral drug. CE methods were developed able to provide the enantioresolution of drug and its separation from the photodegradation products. Enantioresolution was achieved using 5% sulfated-beta-cyclodextrin (S-beta-CD) as chiral selector in 20 mM triethanolammonium phosphate solution (pH 3). The photostability studies were carried out on inclusion complexes of rac-nicardipine with beta-cyclodextrin (beta-CD) and (2-hydroxypropyl)-beta-cyclodextrin (HP-beta-CD) in aqueous solutions (pH 7.4 and 5). The CE analysis of the solutions exposed to UV-A and UV-B radiations showed a photoprotective effect by beta-CD; conversely, HP-beta-CD proved to favor the drug photodegradation. Moreover, evidences for CDs-mediated stereoselective photodegradation of rac-nicardipine were obtained. In fact, two distinct photodegradation profiles were observed for the nicardipine enantiomers in the presence of the CDs. The photodegradation was found to follow an apparent first-order kinetics and two different kinetic constants (k) were obtained for the two enantiomers. After exposure to UV-A and UV-B radiations, the solutions contained residual nicardipine with a significant change in the enantiomeric ratio; this effect was depending on the CD used for the inclusion complexation.

Photostability and phototoxicity studies on diltiazem

The photostability of diltiazem was studied in aqueous solutions at different pH values. Firstly, the hydrolysis of the drug to desacetyldiltiazem in alkaline medium was evaluated and then the drug photodegradation under exposure to UVA-UVB radiation (solar simulator) was monitored by HPLC methods. The main photoproduct was isolated and characterized as diltiazem-S-oxide on the basis of the NMR and mass spectra. The HPLC method was also applied to the selective analysis of diltiazem in commercial formulations. Tests on mutagenicity and photomutagenicity of the drug were also carried out using Salmonella typhimurium TA 102 strain. In this testing the drug neither was mutagenic nor toxic.

Photostability of drugs: photodegradation of melatonin and its determination in commercial formulations

The photostability of melatonin, a hormone used as supplementary drug in the alleviation of jet-lag and other sleep disorders, was studied. The drug photodegradation at different pH values was monitored by HPLC methods. The main photoproduct was isolated and characterised on the basis of the NMR, FTIR, and mass spectra. A HPLC method, in combination with a post-column on-line photochemical derivatisation was developed for the selective and reliable quality control of commercially available melatonin containing products.

PH Effect on the efficiency of the photodeactivation pathways of naphazoline: a combined steady state and time resolved study

The effect of pH on the spectroscopic behavior of naphazoline [NP, 2-(1-naphthylmethyl)imidazoline] has been examined in aqueous solution by combining steady state and time resolved spectroscopic experiments. The photodeactivation pathways are modulated by the pH changes and can be rationalized on the basis of the chemical structure of the compound. The naphthalene-localized singlet formed upon light excitation is partially deactivated via a reversible energy transfer process involving the imidazoline moiety when NP is present in its cationic form. This process leads to an imidazoline-assisted intersystem crossing being responsible for the population of the lowest naphthalene-localized triplet state.In the case of the neutral form, the imidazoline ring behaves as an efficient electron donor, which is able to quench the excited naphthalene via a photoinduced electron transfer. Such a process is responsible for the decrease in the naphthalene-localized triplet generation as well as for the reduction of drug photodegradation.

Cumulative illuminometer and shelf life of drugs in daylight indoors

An instrument used for measuring cumulative illuminance via pulse counting method was introduced. Photodegradation of drugs in daylight and various lamplights was studied. The shelf life of drugs in daylight indoors was predicted with hydroxyprogesterone caproate injection as a model. The cumulative illuminance of unsteady daylight was measured with the patented pulse counting method in the experiment. The equivalent influences of light from different sources on the photostability of the model drug were observed. Results show that the daylight can be replaced by lamplight in photostability studies. The photodegradation of hydroxyprogesterone caproate injection obeys the zero order kinetics: c= c O− k( Et), and its shelf life in daylight indoors is about 1.1 years.

Analysis of nimodipine and its photodegradation product by derivative spectrophotometry and gas chromatography

A derivative spectrophotometric method for the simultaneous determination of nimodipine and its major degradation product in commercial pharmaceutical forms is proposed. The method has been defined on synthetic mixtures and compared with a new gas chromatographic procedure, as a reference method. The UV method has been used to study drug photodegradation in commercial specialities. Both methods, whose results are statistically compared, show satisfactory values of accuracy and reproducibility.